Neuromuscular Junction Morphology as a Biomarker for Therapeutic Efficacy in Myasthenia Gravis

Abstract

The neuromuscular junction (NMJ) is a complex synaptic structure linking the motor nerve to individual skeletal muscle fibers for the regulation of voluntary contraction[4]. Alterations in post-synaptic NMJ morphology are linked to muscle contractile deficits in various pathological conditions (e.g., muscular dystrophy, spinal muscular atrophy, traumatic nerve injury) as well as in aging. In autoimmune mediated Myasthenia Gravis (MG), NMJ morphology is altered by the immunologic degradation of the acetylcholine receptors (AchR’s) and the secondary effects of inflammation. Our work is focused on (1) developing NMJ morphology as a biomarker for the progression of muscle dysfunction in a rat model of MG and (2) determining if clinically effective anti-complement strategies in MG act to preserve NMJ structure. To this end we have established an image analysis pipeline in Nikon Elements to quantify pre- and post-synaptic morphology of the NMJ (bungarotoxin labeled AchR’s) and motor nerve/presynaptic structure (SV2 and neurofilament) in cryosectioned muscle samples. Using this strategy, we have begun to quantitate the change in an experimental rat model of MG and the impact of a clinically effective anti-complement strategy to mitigate these changes.